Various inhibitors of bone resorption (estrogen, diphosphonate compounds, and calcitonin) have been used for treatment of postmenopausal osteoporosis. The effectiveness of these therapeutic agents has been limited by their inhibition of bone formation as well as bone resorption or, in the case of calcitonin, a lack of a stimulatory effect on bone formation. As a result, bone balance after treatment with these agents is only marginally positive, The proposed research will evaluate combined treatments with endocrine or pharmacologic inhibitors of bone resorption and stimulators of bone formation to induce a greater positive bone balance for more effective restoration of lost bone mass in the estrogen-deficient state. The anabolic effects of such combined treatments will be compared to those of treatments with a single therapeutic agent. Development of treatment protocols for restoration of lost bone mass would alleviate orthopedic problems by reducing the incidence of vertebral, wrist, and hip fractures in the elderly female population. Ovariectomized rats will be untreated for the first month after surgery to allow sufficient time for the development of moderate osteopenia. These animals will then be treated with inhibitors of bone resorption (estrogen, the diphosphonate compound EHDP, or calcitonin) and a stimulator of bone formation (parathyroid hormone), singly or in combination, for periods of 30, 60, 90, or 180 days. The skeletal effects of the various treatments will be studied in cancellous bone tissue of the proximal tibial metaphysis by standard bone histomorphometric techniques. Changes in cancellous bone mass and histologic indices of bone formation, resorption, and mineralization will be measured. It is hypothesized that combined treatment with inhibitors of bone resorption and stimulators of bone formation will restore lost bone mass in the estrogen-deficient state. It is further hypothesized that such combined treatments will have a greater positive bone balance and, conse4uently, a greater anabolic effect on the skeleton than treatment with a single therapeutic agent. Validation of these hypotheses will provide a rationale for improved therapies to restore lost bone mass in, osteoporotic patients. Such a finding would mitigate the pain and suffering associated with the orthopedic complications of,osteoporosis in numerous postmenopausal women.